5-azacytidine reverses drug resistance in bladder cancer cells.

Background: Patients with metastatic and muscle-invasive bladder cancer are commonly treated with cisplatin. A significant proportion of patients develop disease progression after an initial response to chemotherapy. Presently there is no standard of care for such patients. We examined whether pretreatment with an epigenetic agent would result in reversal of drug resistance. Materials and Methods: Methylation of proapoptotic and cell cycle genes in bladder cancer cells was examined. Cisplatin- and docetaxel-resistant cells were generated. The effect of target of methylation-induced silencing (TMSI) expression and pretreatment of wild-type and drug-resistant cells with 5-azacytidine on chemosensitivity was determined. Results: Unidirectional crossresistance of cisplatin-resistant UMUC3 cells to docetaxel was observed. Recombinant expression of TMSI or pre-treatment of wild-type and drug-resistant cells with 5-azacytidine resulted in enhanced sensitivity to cisplatin and docetaxel. Conclusion: Our results indicate that epigenetic therapy may restore sensitivity to chemotherapeutic agents in bladder cancer cells.